Saliva of the Ixodes ticks contains numerous immunomodulatory components to aid tick feeding and is a potent delivery vehicle for pathogens, including Biodefense Category C agent tick-borne encephalitis virus and the Lyme disease agent, Borrelia burgdorferi (Bb). In this proposal, we will test our hypothesis that disintegrins from tick saliva inhibit polymorphonuclear leukocyte (PMN) function and thereby provide a survival advantage to vector-borne pathogens. Our plan stems from our previous work, in which we have shown that saliva inhibits PMN adherence and reduces efficiency of pathogen killing through reduction in integrin expression. We will use the novel technology of RNA interference to inhibit the expression of disintegrins in tick salivary glands, as well as recombinant disintegrins, to assess the molecular mechanisms of inhibition of PMN function. We will quantify the effect of disintegrins on markers of PMN activation, production of inflammatory mediators, and signaling pathways in vitro. In addition, we will address the role of disintegrins on PMN function in the skin using the murine model of Lyme disease. The greater significance of this work is the identification of a mechanism of saliva's inhibition of PMN that can be exploited by therapeutic interventions to improve host immunity against vector-borne pathogens, including those of Biodefense concern. [unreadable] [unreadable] [unreadable]